1. Field of the invention
The present invention relates to disinfection useful for preventing infection with retroviruses.
More particularly, the present invention relates to a disinfectant composition for retroviruses containing as active ingredient a natural or synthetic oligo- or polysaccharide having at least one S-oxoacid group attached to the saccharic carbon atom through a linking group of lower molecular weight, the manufacture and method of use thereof. The said composition is effective against retroviruses, especially causative viruses for AIDS (acquired immuno deficiency syndrome), ARC(AIDS-related complex), PGL (persistent generalized lymphadenopathy) and LAS (lymphadenopathy syndrome).
Retroviruses refer to a family of viruses which have RNA and reverse transcriptase (RNA-dependent DNA polymerase), of which the latter is essential to the first stage of its self-replication for synthesizing complementary DNA on the base of template RNA of the virus.
Retroviruses include various oncoviruses such as avian leukemia virus, avian sarcoma virus, avian reticuloendotheliosis virus, murine mammary cancer virus, murine leukemia virus, murine sarcoma virus, guinea pig type C virus, hamster type C virus, rat leukemia virus, feline leukemia virus, feline sarcoma virus, feline type C virus, ovine leukemia virus, bovine leukemia virus, swine type C virus, simian leukemia virus, Mason-Pfizer virus, simian sarcoma virus, simian T-lymphotropic virus, baboon type C virus, and the like. Among those infective to human, those important are adult T-cell leukemia virus (ATLV), or human T-lymphotropic virus type I (HTLV-I), and type II (HTLV-II). The adult T-cell leukemia abounds in Japan, especially in the west part, but the effective treatment containing prevention and therapeutics of the disease has not been established.
On the other hand, retroviruses also include those having no oncogenecity, such as visna virus, ovine progressive pneumonia virus, ovine maedi virus, simian T-lymphotropic virus type III (STLV-III), equine infectious anemia virus, and the like. The viruses isolated from human as causative agents for AIDS, ARC, PGL and LAS (so-called AIDS-viruses such as HTLV-III, LAV1, LAV2, ARV and HTLV-IV) belong to this subfamily. Recently, AIDS-causative viruses are called HIVs (human immuno deficiency viruses).
Further, as the third subfamily, there is known a spumavirinae to which simian foaming virus belongs. Also, a retrovirus has been isolated recently as a causative virus for Kawasaki disease (mucocutaneous lymphonode syndrome).
World-wide interests have been focused on AIDS due to its unfavorable prognosis. It is a clinical syndrome characterized by recurrent oppotunistic infections, (e.g. pneumocystis carinii pneunonia, cryptococcal meningitis, disseminated toxoplasmosis), lymphadenopathy, and an aggressive Kaposi's sarcoma, and induces a high mortality more than 90% by the dysregulation of immune system. It is also known that the helper-T cells are specifically destroyed by the infection of the virus. Further, among the conditions related with AIDS viruses, there are a carrier who exhibits no disease conditions, PGL (persistent generalized lymphadenopathy), LAS (lymphadenopathy syndrome), ARC(AIDS-related complex), etc.
In order to find out substances effective against causative viruses for AIDS, PGL, LAS and AIDS-virus carrier, the present inventors, using a cell line of MT-4 established from T-cells of adult T-cell leukemia patient and HTLV-III which is a causative virus for AIDS, examined the effects of various substances on the infection and replication of HTLV-III.
The above MT-4 cell line is absolutely susceptible to the infection with HTLV-III which causes and followed by cell lysis (experimental HTLV-III infection). The present inventors found that when certain polysaccharides having a sulfonate group (--SO.sub.3.sup.-) or mucopolysaccharides having a sulfonate group or the sulfuric acid esterified substances thereof were added to the experimental HTLV-III infection system, the infection of HTLV-III on MT-4 cells and viral replication were strongly inhibited without accompanying any toxicity to the cells.
Further, the present inventors demonstrated that the above polysaccharides inhibit the reverse transcriptase of the retroviruses including AIDS virus in vitro, prevent the adsorption of such viruses to the target cells and inhibit cell fusion of virus-infected cells to noninfected cells, thereby suppressing the replication of the virus.
2. Description of related art
Among the sulfuric acid esters of polysaccharides, dextran sulfate having a lower molecular weight has long been commercially available as an antilipemic or anti-arteriosclerosis agent. Also, dextran sulfate having a relatively higher molecular weight is known to have an inhibitory action against herpes virus. (European Patent Publication No.0066379). However, since the herpes virus is a DNA virus, its replication is absolutely different from that of the retrovirus which depends entirely on reverse transcriptase for synthesis of DNA. Accordingly, the effectiveness of dextran sulfate on herpes virus does not necessarily mean its effectiveness on retrovirus. Furthermore, dextran sulfate having a lower molecular weight less than 10,000 was found to be almost ineffective on herpes viruses.
Among the mucopolysaccharides or these sulfates, chondroitin sulfate is commercially available as a drug for sensorineural hearing impairment, neuralgia, lumbago and chronic nephritis, and also as a cornea-protective ophthalmic solution. Keratan sulfate is obtainable from the cartilage, teichuronic acid from the cell walls of Bacillus subtilis, hyaluronic acid from shark skin, whale cartilage, or from human serum, heparan sulfate from bovine liver or lung, and chitin from arthropod or from fungus or yeast, respectively. The preparation process for the further sulfuric acid esterified compound of chondroitin sulfate is described in Japanese Patent Publication (JP, B2) No.9570/1971.
Heparin is known to inhibit various enzymes in vitro, e.g., DNA polymerase of phytohemagglutinin stimulated human lymphocytes and reverse transciptase of simian sarcoma virus (Cancer Research, 38, 2401 2407), but is not proved to inhibit the viral infection of cells.